KR19980063026A - Method for preparing porous matrix type sustained release formulation by emulsion method - Google Patents

Abstract

When the aqueous solution containing the drug is dispersed and stirred in an organic solution in which a polymer compound and a surfactant are dissolved in an organic solvent, it is made into an emulsion, and then formed into a desired matrix form and immediately lyophilized or when the surface of the matrix starts to cure at room temperature. After drying to vacuum drying again characterized in that for producing a porous matrix.

Description

Method for preparing porous matrix type sustained release formulation by emulsion method

1 is a photograph taken with a scanning electron microscope before drug release of a film cross-section containing 50% of gentamicin in the porous matrix-type sustained-release preparation of the present invention.

FIG. 2 is a photograph taken with a scanning electron microscope after drug release of a film section containing 50% of gentamicin in the porous matrix-type sustained-release preparation of the present invention.

3 is a graph of the initial release over time of the porous matrix sustained release formulation of the present invention.

4 is a zero-order release graph for long-term release over time of the porous matrix type sustained release preparation of the present invention.

5 is a release graph according to the concentration change of Span 80 in the porous matrix type sustained-release preparation of the present invention.

6 is a photograph taken with a scanning electron microscope of a cross section of the film as an example of the porous matrix sustained-release preparation of the present invention.

7 is a release graph containing 35% by weight of gentamicin sulfate in the porous matrix-type sustained-release preparation of the present invention.

FIG. 8 is a photograph taken by a scanning electron microscope of a film section containing 20% by weight of ethylene-vinyl acetate and 35% by weight of gentamicin sulfate in the porous matrix-type sustained-release preparation of the present invention.

The present invention is capable of sustained release of a drug while having various porosities by emulsifying an organic solution in which a fat-soluble polymer compound is dissolved in an organic solvent and a surfactant to emulsify a water-soluble drug dissolved in water. A new and advanced process for the preparation of controllable matrix formulations.

The matrix-type sustained release preparation of the present invention can be usefully used as a medical therapeutic agent because it can release the drug at a constant rate and for a certain period as a matrix preparation for oral or parenteral administration.

An emulsion refers to a state in which fine particles of a liquid are uniformly dispersed in another liquid which does not dissolve it. Generally, a surfactant is used to maintain an emulsion state.

Sustained release refers to a property that releases the drug release from the drug-containing preparation according to a pre-designed time program, which increases the effectiveness of the drug and reduces side effects. A generic term refers to a formulation in which a drug is dissolved or dispersed uniformly or non-uniformly in a matrix.

Release of water-soluble drugs from general insoluble matrix formulations and slower degradation matrix formulations usually occurs at first order kinetics and exhibits a slowing release pattern over time [Higuchi T., J. Pharm. Sci, 50, 874-875 (1961), Higuchi T., J. Pharm, Sci, 52, 1145-1149 (1063), Manduit et al, J. Controlled Release, 25, 43-49 (1993). In addition, when a water-soluble drug is imposed at the hydrophobic polymer matrix below the percolation threshold, since the water-soluble drug hardly passes through the hydrophobic matrix, the drug is released after a predetermined amount of the drug exposed to the surface is initially released. This rarely occurs and after many hours the drug remains unreleased. If the drug load is higher and higher than the exudation threshold, the release rate depends on the solubility of the drug in the body fluid and the diffusion through the channel formed by the drug dissolving in contact with the body fluid, so that the low molecular weight drug having high solubility in water In the case of high release rates and high release rates (Siegel et al, J. Controlled Release, 8, 223-236 (1989), Sltzman et al, J. Biophys., 55, 163-171 (1989)). .

In the case of dispersing a water-soluble drug that induces high osmotic pressure in an insoluble polymer matrix, when exposed to an aqueous solution, the water-soluble drugs exposed on the surface rapidly dissolve to form a channel, which is initially released and is separated from the channel. They are known to be sustained release by breaking the polymer matrix wall around the drug that acts as an osmotic agent and act as a semipermeable membrane [Amsden et al, J. Controlled Release, 30, 45 ~ 56 (1994), Amsden BG and Cheng Y., J. Controlled Release, 31, 21 ~ 32 (1994)] The use of drugs with high osmotic pressures can release the drug lower than the effusion threshold and release the drug in a sustained manner. It can also be reduced.

However, if the polymer matrix surrounding the drug is too thick, the moisture passing through the polymer phase to the drug is very low and the polymer matrix wall is not likely to break due to osmotic pressure, so the drug is simply dispersed in the matrix. The formulation is very slow in the release of the drug, or more drug is left without release [Zhang et al, J. Pharm. Pharmacol. 46, 718-274 (1994), Amsden BG and Cheng Y., J. Controlled Release, 31, 21-32 (1994).

In general, when imposing a water-soluble drug on a hydrophobic matrix, the drug is dispersed in an organic polymer solution, or evenly mixed with a drug and a polymer in a solid state, then extruded or pressed at high temperature. Because of the limitations, the rate of drug release appears uneven over time.

The present invention will be described in more detail by using an oil-soluble surfactant to make the water-soluble drug dispersed in the hydrophobic polymer matrix evenly by an emulsion method, and at the same time, the surfactant alone or the surfactant and the polymer matrix together act as a semipermeable membrane. This method relates to a method of making most of the drugs contained in the matrix release by shortening the distance of the matrix of water by the porosity of the matrix while allowing the water-soluble drug to be released slowly even by relatively low osmotic pressure.

In order to achieve the above object, the present invention disperses and stirs an aqueous solution containing a drug in an organic solution in which a polymer compound and a surfactant are dissolved in an organic solvent, and then forms an emulsion, and immediately freeze-dried or room temperature ( 16 ℃ ~ 30 ℃), depending on the boiling point of the organic solution for a certain time, but dried until the surface of the matrix starts to harden, and then vacuum-dried (0.75 mmHg or less) to remove the organic solvent and water to prepare a porous matrix-type formulation It is.

As the polymer compound used in the matrix of the present invention, a polylactide, a lactide-glycolide copolymer, a silicone rubber, an ethylene-vinylacetate copolymer, a poly-ortho-ester polymer, and the like can be used. Polylactide is a homopolymer with a number average molecular weight of 100,000, which is widely used as a biocompatible biodegradable material such as a tide-glycolide copolymer as a raw material for suture. Polyscience, Inc. The product (Examples 1, 2, 3), and the lactide-glycolide copolymer were prepared using Resomer RG858 (Example 4) from Boehringer Ingelheim, Germany. The ethylene-vinylacetate copolymer, which is known to be biodegradable but has a good biosynthesis, was manufactured from Aldrich Chemical Company, Inc. (Example 5) of USA, which contains 33% of vinyl acetate.

Surfactants that can be used in the present invention are fatty acid-based, olefin-based, alkylcarbonyl-based, silicone-based, sulfate ester-based, petal alcohol sulfate-based, sulfate-pet and oil-based, sulfonate-based, aliphatic sulfonate-based, alkylaryl sulfo Nate type, ligmine sulfonate type, phosphoric acid ester type, polyoxyethylene type, polyoxyethylene caster oil type, polyglycerol type, polyol type, imida group type, altanolamine type, hetamine type, sulfobeccamin type , Phosphatide-based, polyoxyethylene- sorbitan fatty acid ester-based (Tween-based), sorbitan ester-based (Span-based) and the like can be used, but preferably sorbitan ester-based, sorbitan monooleate (span 80) ) Is used. The concentration is suitably 0.1 to 5% by weight relative to the emulsion solution. According to the type and concentration of the surfactant, the release rate of the drug, that is, the amount of release of the drug changes with time (Example 2). The range of use of the surfactant is limited as above, because it is too thin to emulsify below this concentration, the release rate of the drug is too slow at higher concentrations and there is a risk of side effects in clinical applications.

Drugs that can be used in the present invention include analgesics, anti-inflammatory drugs, antiparasitic agents, arrhythmia treatments, antibiotics, anticoagulants, antidepressants, diabetes treatments, anticoagulants, antibacterial agents, antigout agents, antihypertensive drugs, antipyretics, heart disease drugs, hormone drugs, asthma drugs , Bronchotherapy, diuretics, constipation, digestive system treatments, sedatives, sleeping pills, anesthetics, nutrition and tonics, preservatives, preservatives, stabilizers, insecticides, fungicides, muscle relaxants, tuberculosis and leprosy medicine, urinary system drugs, circulatory system drugs, bexin A wide range of drugs can be used, and water-soluble drugs having a solubility of at least 1 mg / ml are preferred depending on the effective concentration of the drug. If the drug is low solubility, the amount that can be charged to the emulsion is too small.

Organic solvents usable in the present invention include butyl alcohol, chloroform, cyclohexane, dichloromethane, dichloroethane, ethyl acetate, ethyl ether, dipropyl ether, toluene and the like.

In the present invention, the volume ratio of the aqueous solution and the organic solvent is preferably 1: 2 to 1: 40, but the initial release of the drug increases as the volume ratio of the aqueous solution is increased. The reason for delimiting the volume ratio of the aqueous solution and the organic solvent is that the emulsion cannot be formed well if the volume ratio of the aqueous solution is too high. If the emulsion is formed, the initial release of the drug is too high and the volume ratio of the aqueous solution is too small. This is because the amount of drug that can be dissolved is too small. Matrix shape of the present invention can be produced in various ways, such as film, surface coating, pellets, tablets, plates, columnar.

As the emulsification method of the present invention, a stirrer, a vortex stirrer, a homogenizer, an ultrasonic device, a microfluidizer, or the like can be used according to a known method.

Next, a preferred embodiment of the present invention will be presented. However, the following examples are provided to more easily understand the present invention, and the scope of the present invention is not limited to these examples.

Example 1

An aqueous solution in which gentamicin is dissolved at a concentration of 50% in a polymer solution dissolved in dichloromethane at a concentration of 16% poly-L-lactide (number average molecular weight of 100,000) and span 80 at 3% (weight%) Gentamicin is added to 20% of the weight of poly-L-lactide to homogeneously emulsify using a vortex stirrer, stirrer and sonicator, and then applied onto a glass plate and applied to a 1 mm high applicator. To make a film of uniform thickness, dried at room temperature for 4 hours and vacuum dried for another 24 hours to prepare a film, and the film before the drug was released and the film after the drug was released were observed with a scanning electron microscope. . It was confirmed that the film has a porosity by the water contained in the emulsion (see FIGS. 1 and 2).

Drug Release Example

Except that the concentration of the gentamicin aqueous solution in Example 1 was changed to 25%, 35%, 50% was substantially the same as in Example 1, the film was cut to the same size PBS of pH 7.4 Released the drug.

Comparative Example 1: Initial Release

It can be seen that the initial release of the drug increases as the amount of water contained in the emulsion increases (see FIG. 3).

Comparative Example 2: Zero-Order Release for Long Period

It can be seen that zero release is maintained over a long period after the initial release of the drug (see FIG. 4).

Example 2

A film was prepared in substantially the same manner as in Example 1 except that the concentration of the gentamicin aqueous solution was changed to 35% in Example 1, and the concentration of span 80 was changed to 0.5%, 1%, 1.5%, and 3%. The prepared film was cut to the same size to release the drug in PBS at pH 7.4. It was found that the initial release of the drug and the free rate of the drug were changed according to the concentration of the span. (See Figure 5)

Example 3

An aqueous solution in which Cytoxim sodium was dissolved at a concentration of 10% by weight in a polymer solution in which poly-L-lactide (number average molecular weight of 100,000) was dissolved in methylene chloride at a concentration of 16% by weight and span 80 at 1% by weight. The weight of the Celltaxim sodium is added to 20% of the weight of the lactide-glycolide copolymer and homogenized using a vortex stirrer, a stirrer and a sonicator, and then uniformly emulsified and applied on a glass plate and 1 mm high. The film was pushed with an applicator to make a film of uniform thickness, and dried at room temperature for 4 hours, and then vacuum dried for 24 hours to prepare a film, and the film was observed with a scanning electron microscope. It was confirmed that the film has porosity by the water contained in the emulsion. (See FIG. 6).

Example 4

Lactide-glycolide copolymer (Resomer RG858, Boehringer Ingelheim, Germany) and poly-D, L-lactide (Resomer R207, Boehringer Ingelheim, Germany) were 16% by weight and Span 80 at 1% by weight. To a polymer solution dissolved in chloroform at a concentration, an aqueous solution of gentamicin sulfate at a concentration of 35% by weight was added so that the weight of the gentamicin sulfate was 20% of the weight of the lactide-glycolide copolymer. And homogenous emulsifier using a sequential slurry and a sonicator, then applied on a glass plate and pushed onto a 1 mm high applicator to make a film of uniform thickness, followed by drying at room temperature for 4 hours and again vacuum drying for 24 hours. The film was prepared, cut to the same size to release the drug in PBS at pH 7.4. The use of lactide-glycolide copolymers or poly-D, L-lactide can also be seen as a sustained release of the drug, especially when poly-D, L-lactide is used. It can be observed that the glass velocity is faster than when using (see FIG. 7).

Example 5

20 wt% of the ethylene-vinylacetate copolymer (weight average molecular weight 130,000, ethylene: vinylacetate = 67:33) and 1 wt% of span 83 were 35 wt% of the gentamicin sulfate in the polymer solution dissolved in chloroform. The aqueous solution dissolved in% was added so that the weight of gentamicin sulfate was 20% by weight relative to the weight of the ethylene-vinylacetate copolymer, and the mixture was emulsified homogeneously using a vortex stirrer, a stirrer and a sonicator sequentially. The film was coated on a glass plate and pushed with an applicator having a height of 1 mm to make a film having a uniform thickness. The film was then dried at room temperature for 4 hours and then vacuum dried for 24 hours, and observed by a scanning electron microscope. It was confirmed that the film has porosity by the water contained in the emulsion. (See FIG. 8).

Claims (7)

An aqueous solution containing a drug is dispersed and stirred in an organic solvent in which a polymer compound and a surfactant are dissolved to form an emulsion, which is then formed into a desired matrix form and dried at a low temperature or room temperature until freeze-drying or until the surface of the matrix starts to harden. Method for producing a porous matrix type preparation, characterized in that the vacuum drying to remove the organic solvent and water The method of claim 1, wherein a polylactide or a lactide-glycolide copolymer is selected and used as the polymer compound. The method according to claim 1, wherein a sorbitan ester (Span) is used as the surfactant. The method for preparing a porous matrix formulation according to claim 1, wherein a pharmaceutical preparation for parenteral or oral administration prepared by dissolving a water-soluble drug in an internal aqueous solution of the emulsion is used. The method for producing a porous matrix formulation according to claim 1, wherein the organic solvent is selected from dichloromethane and chloroform. The method according to claim 1, wherein the volume ratio of the aqueous solution and the organic solvent is in the range of 1: 2 to 1:40. The method according to claim 1, wherein the amount of the surfactant added is 0.1 to 5% by weight of the organic solvent.